scholarly journals An ApoA-I Mimic Peptide of 4F Promotes SDF-1α Expression in Endothelial Cells Through PI3K/Akt/ERK/HIF-1α Signaling Pathway

2022 ◽  
Vol 12 ◽  
Author(s):  
Kaixuan Lv ◽  
Lingyu Kong ◽  
Mei Yang ◽  
Linlin Zhang ◽  
Shangmin Chu ◽  
...  

Atherosclerosis (AS) seriously impairs the health of human beings and is manifested initially as endothelial cells (ECs) impairment and dysfunction in vascular intima, which can be alleviated through mobilization of endothelial progenitor cells (EPCs) induced by stromal-cell-derived factor-1α (SDF-1α). A strong inverse correlation between HDL and AS has been proposed. The aim of the present work is to investigate whether 4F, an apolipoprotein A-I (apoA-I, major component protein of HDL) mimic peptide, can upregulate SDF-1α in mice and human umbilical vein endothelial cells (HUVECs) and the underlying mechanism. The protein levels of SDF-1α were measured by ELISA assay. Protein levels of HIF-1α, phosphorylated Akt (p-Akt), and phosphorylated ERK (p-ERK) were evaluated by Western blotting analysis. The results show that L-4F significantly upregulates protein levels of HIF-1α, Akt, and ERK, which can be inhibited by the PI3K inhibitor, LY294002, or ERK inhibitor, PD98059, respectively. Particularly, LY294002 can downregulate the levels of p-ERK, while PD98059 cannot suppress that of p-Akt. D-4F can upregulate the levels of HIF, p-Akt, and p-ERK in the abdominal aorta and inferior vena cava from mice. These results suggest that 4F promotes SDF-1α expression in ECs through PI3K/Akt/ERK/HIF-1α signaling pathway.

Author(s):  
Hongru Lin ◽  
Xuehan Wu ◽  
Yaqin Yang ◽  
Ziwei Wang ◽  
Weilu Huang ◽  
...  

Inflammation-induced activation and dysfunction of endothelial cells play an important role in the pathology of multiple vascular diseases. Nicaraven, a potent hydroxyl radical scavenger, has recently been found to have anti-inflammatory roles. However, the mechanism of its action is not fully understood. Here we investigated the effects of Nicaraven on TNFα-induced inflammatory response in human umbilical vein endothelial cells (HUVECs) and explore the underlying mechanisms related to NF-κB signaling pathway. Our results showed that Nicaraven significantly reduced the reactive oxygen species production after TNFα stimulation. Nicaraven suppressed TNFα-induced mRNA expression of multiple adhesion molecules and pro-inflammatory cytokines, including VCAM-1, ICAM-1, E-selectin, MCP-1, TNFα, IL-1β, IL-6 and IL-8. In addition, Nicaraven inhibited monocyte adhesion and reduced the protein levels of VCAM-1 and ICAM-1. Mechanistically, Nicaraven prevented TNFα-induced activation of NF-κB signaling pathway by suppressing the phosphorylation of NF-κB p65, IκBα, and IKKα/β, stabilizing IκBα, and inhibiting the translocation of p65 from cytosol to nucleus. Finally, we showed that Nicaraven improved the functions of endothelial cells, seen as the up-regulation of endothelial nitric oxide synthase and increased nitric oxide levels. Our findings indicated that Nicaraven effectively inhibits TNFα-induced endothelial activation and inflammatory response at least partly through inhibiting NF-κB signaling pathway.


2019 ◽  
Vol 20 (21) ◽  
pp. 5383 ◽  
Author(s):  
Li Zhang ◽  
Feifei Wang ◽  
Qing Zhang ◽  
Qiuming Liang ◽  
Shumei Wang ◽  
...  

Inflammation is a key mediator in the progression of atherosclerosis (AS). Benzoinum, a resin secreted from the bark of Styrax tonkinensis, has been widely used as a form of traditional Chinese medicine in clinical settings to enhance cardiovascular function, but the active components of the resin responsible for those pharmaceutical effects remain unclear. To better clarify these components, a new phenylpropane derivative termed stybenpropol A was isolated from benzoinum and characterized via comprehensive spectra a nalysis. We further assessed how this phenylpropane derivative affected treatment of human umbilical vein endothelial cells (HUVECs) with tumor necrosis factor-α (TNF-α). Our results revealed that stybenpropol A reduced soluble intercellular cell adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), interleukin-8 (IL-8), and interleukin-1β (IL-1β) expression by ELISA, inhibited apoptosis, and accelerated nitric oxide (NO) release in TNF-α-treated HUVECs. We further found that stybenpropol A decreased VCAM-1, ICAM-1, Bax, and caspase-9 protein levels, and increased the protein levels of Bcl-2, IKK-β, and IκB-α. This study identified a new, natural phenylpropane derivative of benzoinum, and is the first to reveal its cytoprotective effects in the context of TNF-α-treated HUVECs via regulation of the NF-κB and caspase-9 signaling pathways.


PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256646
Author(s):  
Harsha Nagar ◽  
Seonhee Kim ◽  
Ikjun Lee ◽  
Su-Jeong Choi ◽  
Shuyu Piao ◽  
...  

Rho GDP-dissociation inhibitor (RhoGDI), a downregulator of Rho family GTPases, prevents nucleotide exchange and membrane association. It is responsible for the activation of Rho GTPases, which regulate a variety of cellular processes, such as migration. Although RhoGDI2 has been identified as a tumor suppressor gene involved in cellular migration and invasion, little is known about its role in vascular endothelial cell (EC) migration. CR6-interacting factor 1 (CRIF1) is a CR6/GADD45-interacting protein with important mitochondrial functions and regulation of cell growth. We examined the expression of RhoGDI2 in CRIF1-deficient human umbilical vein endothelial cells (HUVECs) and its role in cell migration. Expression of RhoGDI2 was found to be considerably higher in CRIF1-deficient HUVECs along with suppression of cell migration. Moreover, the phosphorylation levels of Akt and CREB were decreased in CRIF1-silenced cells. The Akt-CREB signaling pathway was implicated in the changes in endothelial cell migration caused by CRIF1 downregulation. In addition to RhoGDI2, we identified another factor that promotes migration and invasion of ECs. Adrenomedullin2 (ADM2) is an autocrine/paracrine factor that regulates vascular tone and other vascular functions. Endogenous ADM2 levels were elevated in CRIF1-silenced HUVECs with no effect on cell migration. However, siRNA-mediated depletion of RhoGDI2 or exogenous ADM2 administration significantly restored cell migration via the Akt-CREB signaling pathway. In conclusion, RhoGDI2 and ADM2 play important roles in the migration of CRIF1-deficient endothelial cells.


2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Liting Wang ◽  
Yuxia Zhang ◽  
Yujia Wang ◽  
Rining Tang

Abstract Background and Aims The characteristics of valvular calcification (VC) in early stage are extracellular matrix (ECM) accumulation and muti-cells activation. In our previous work, we found high-phosphorus (HP) diet aggravated ECM accumulation in both aortic valve and mitral valve in rats with chronic kidney disease (CKD). However, the underlying mechanism of HP contribution in ECM accumulation of CKD-induced VC is still unknown. Method canine valvular interstitial cells (VICs), valvular endothelial cells (VECs) and human umbilical vein endothelial cells (HUVECs) were used in this study. CKD mice (C57b and Tek-EGFP-PolyA) was build by 0.2% adenine-diet for 6 weeks and HP diet/NP diet for 10 weeks. Results As for VICs, HP induced qVICs transfer into aVICs, not oVICs, which was characterized with upregulated level of smoothelin and viemitin. There was no calcium accumulation was observed, suggesting that VICs do not have the ability to synthesize calcium crystals under pure HP intervention. As for VECs, aVICs activated by HP induced VECs EndMT in a transwell-assay, which was characterized with decreasing protein levels of endothelial markers (CD31, vWF, VE-cadherin) and increasing protein levels of mesenchymal makers (α-SMA, FSP1, N-cadherin). Then, IL-8 was found as the main factor releasing from VICs to induce VECs EndMT. In vitro, the concentration of IL-8 in the lower chamber could reach 2-4ng/ml. Reparixin was used to inhibit IL-8 receptor of VECs, which could relive aVICs-induced EndMT. In vivo, the expression of valve CXCL-2 (the mouse IL8 functional homolog) was increased in HP-diet compared with NP-diet, though the serum level of CXCL-2 was similar between two groups. AAV9-sm22a-CXCL-2 and Reparixin could inhibit VECs EndMT by inhibiting VICs relasing CXCL-2 and inhibiting VECs IL-8 receptor in CKD mice of Tek-EGFP-PolyA respectively. Then, IL-8 was found to induced VECs EndMT by miR-214-3p/PTEN/Akt pathway. Inhibiting EndMT by blocking IL-8/miR-214-3p could alleviate ECM accumulation. Conclusion HP could induce qVICs transfer into aVICs, and aVICs could cause VECs EndMT via IL-8/miR-214-3p/PTEN/Akt pathway. Both take part in ECM accumulation in CKD-induced VC.


2019 ◽  
Vol 20 (3) ◽  
pp. 458 ◽  
Author(s):  
Fernanda Ursoli Ferreira ◽  
Lucas Eduardo Botelho Souza ◽  
Carolina Hassibe Thomé ◽  
Mariana Tomazini Pinto ◽  
Clarice Origassa ◽  
...  

The endothelial-to-mesenchymal transition (EndMT) is a biological process where endothelial cells (ECs) acquire a fibroblastic phenotype after concomitant loss of the apical-basal polarity and intercellular junction proteins. This process is critical to embryonic development and is involved in diseases such as fibrosis and tumor progression. The signaling pathway of the transforming growth factor β (TGF-β) is an important molecular route responsible for EndMT activation. However, it is unclear whether the anatomic location of endothelial cells influences the activation of molecular pathways responsible for EndMT induction. Our study investigated the molecular mechanisms and signaling pathways involved in EndMT induced by TGF-β2 in macrovascular ECs obtained from different sources. For this purpose, we used four types of endothelial cells (coronary artery endothelial cells, CAECs; primary aortic endothelial cells PAECs; human umbilical vein endothelia cells, HUVECs; and human pulmonary artery endothelial cells, HPAECs) and stimulated with 10 ng/mL of TGF-β2. We observed that among the ECs analyzed in this study, PAECs showed the best response to the TGF-β2 treatment, displaying phenotypic changes such as loss of endothelial marker and acquisition of mesenchymal markers, which are consistent with the EndMT activation. Moreover, the PAECs phenotypic transition was probably triggered by the extracellular signal–regulated kinases 1/2 (ERK1/2) signaling pathway activation. Therefore, the anatomical origin of ECs influences their ability to undergo EndMT and the selective inhibition of the ERK pathway may suppress or reverse the progression of diseases caused or aggravated by the involvement EndMT activation.


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